Citations

Abstract Background Stroke is a time-sensitive neurological emergency in which early EMS activation and presentation to definitive care are cornerstones of effective therapy. Large language models (LLMs) are increasingly consulted by the public for medical advice, but the veracity of the guidance provided by commercially available models responding to potential stroke symptoms is not well understood. Methods We performed a cross-model benchmarking study comparing the triage choices of three frontier LLMs (Claude Sonnet 4.6, GPT-4o, and Llama 3.3-70b-versatile) on first-person vignettes describing a unilateral arm symptom on waking, across 10 symptom descriptors, and two clinical phases (before and after a partially reassuring self-examination), with or without a clinical distractor (n=50 per condition). Results Claude sought emergency care most often, Llama least, and GPT-4o in between, diverging most sharply in the post-examination phase where Claude called 911 in 100% of runs, Llama called for non-emergency help in 100%, and GPT-4o was symptom-dependent. A distractor shifted behavior away from emergency care in almost all conditions: calling 911 fell from 37.9% to 14.6% and waiting rose from 0% to 45.9% in the post-examination vignette. Responses were also sensitive to symptom word: weak, limp, heavy, and clumsy generated higher alarm, whereas numb, tingly, odd, strange, and weird generated less urgent responses. Conclusions The increasing use of LLMs for medical advice has significant public health implications. Commercially available LLMs show significant model-to-model variability and framing sensitivity when confronted with potential stroke symptoms, including under-recognition of canonical CDC warning descriptors, underscoring the need for systematic benchmarking as these tools become de facto first points of contact for patients experiencing neurological emergencies.

Objectives: To summarize current evidence for radiotherapy in the treatment of OA. The population, intervention, comparator, and outcome questions included: What is the role of LDRT for treatment of OA?; What are risks of LDRT?; and What are the optimal RT techniques for OA? Methods: This multispecialty-led committee includes radiation oncologists, rheumatologists, orthopedic surgeons, and a patient advocate. Using the population, intervention, comparator, outcome, timing and study design (PICOTS) framework, evidence regarding treatment outcomes was assessed using Cochrane and PRISMA methodology. Eligible studies included prospective and retrospective (n≥50) studies published between January 1, 2010, and May 10, 2025, from Embase, Medline, and PubMed databases. Study type and quality were assessed. Well-established RAND-UCLA consensus methodology (modified Delphi) was used to rate the appropriateness of the treatment options. Results: Of the 548 articles identified using the search strategy, 44 were selected for inclusion. Eight additional studies were identified through backward citation searching. Ten well-designed studies accounting for biases, 15 moderately well-designed studies accounting for the most common biases, 18 studies with design limitations, 8 supplemental studies not useful as primary evidence, and 1 meta-analysis were included. Additional studies were included to provide context and were not used to guide recommendations. The results of this analysis demonstrate that LDRT results in an overall treatment response rate of 60% to 90%, with significant clinical benefits including pain reduction, increased joint mobility, and improved quality of life. Conclusions: This systematic review and consensus guidelines for LDRT treatment of OA are based on current evidence. Further high-quality studies are warranted.

Abstract Heart involvement in eosinophilia represents a rare entity with substantial cardiac morbidity and mortality. This disorder is often overlooked and diagnosed in its advanced stages. In a subgroup of patients with eosinophilic heart disease, peripheral blood eosinophilia may not be present, and the biopsy of the affected organ or tissue is essential to establish the correct diagnosis. In this clinical consensus statement, an expert consensus group reviews the epidemiology, aetiology, diagnosis, and management of eosinophilic heart disease. The aim of the document is to increase awareness about the cardiac involvement associated with eosinophilia in order to diagnose the disease in early phases and prevent deleterious heart damage and adverse outcomes of affected individuals. The spectrum of physiological and immunological derangements requires a multidisciplinary approach for optimal management of affected individuals.

OBJECTIVE The objective was to evaluate the trajectories of hematoma resolution and functional improvement after middle meningeal artery embolization (MMAE) for chronic subdural hematoma (cSDH), model the temporal pattern of cSDH resolution, and identify factors associated with favorable outcomes. METHODS This real-world multicenter retrospective study included cSDH patients treated with MMAE at 24 centers between 2019 and 2024. Hematoma thickness was measured at baseline and at follow-up intervals (1–4 weeks, 1–3 months, 3–6 months, 6–12 months, and > 12 months after embolization). Resolution patterns were modeled using exponential decay functions. Modified Rankin Scale (mRS) scores assessed functional outcomes. Good functional outcome was defined as mRS score ≤ 2. Resolution patterns were modeled using exponential decay functions to estimate time to 50% and 80% reduction. Patients were categorized as complete resolution (≥ 99%) or by quartile of the remaining distribution (substantial [73%–98%], moderate [53%–73%], partial [27%–53%], minimal [< 27%]). The primary outcome was good functional status (mRS score ≤ 2). RESULTS The authors analyzed a total of 1781 patients with 2295 cSDHs who underwent MMAE. The mean ± SD age was 72.8 ± 12.4 years and 68.1% of patients were male. The initial mean hematoma thickness was 15.31 ± 6.53 mm, decreasing to 5.24 ± 5.91 mm at final follow-up (mean reduction 64.3% ± 42.1%). Resolution followed an exponential decay pattern, with an estimated time to 50% reduction of 1.8 months and to 80% reduction of 8.9 months. Complete resolution occurred in 1031 of 2224 patients (46.4%) with complete follow-up. The median (IQR) mRS score improved from 1 (0–3) at baseline to 0 (0–2) at > 12 months. Good functional outcomes were more common in patients with complete versus minimal resolution (68.9% vs 35.0%, p < 0.001). Achieving ≥ 73% resolution within 90 days was associated with better outcomes (good outcome in 76.9% of those with ≥ 73% resolution vs 67.3% in those without, p < 0.001). Neurological deterioration was the strongest predictor of lack of good outcome (23.7% in patients with neurological deterioration vs 82.4% without, p < 0.001). CONCLUSIONS After MMAE for cSDH, reduction in hematoma thickness follows a predictable exponential decay pattern. Greater extent (≥ 80%) and faster timing (within 90 days) of resolution are valuable prognostic indicators. Functional outcomes improve progressively through 6–12 months after the procedure. The relationship between resolution extent and functional outcomes provides quantitative benchmarks for evaluating treatment response.

Background: Hypoplastic left heart syndrome (HLHS) is defined as “a spectrum of congenital cardiovascular malformations with normally aligned great arteries without a common atrioventricular junction, characterized by underdevelopment of the left heart with significant hypoplasia of the left ventricle including atresia, stenosis, or hypoplasia of the aortic or mitral valve, or both valves, and hypoplasia of the ascending aorta and aortic arch”. Without treatment, HLHS is usually lethal in the neonate. Many hypotheses have been advanced to explain the etiology of HLHS; however, no single theory appears to fully explain the phenotypic variability seen in HLHS. Furthermore, many of these theories offer no explanations regarding the precipitating events which lead to the development of HLHS. Objective: This review considers and critically evaluates the strengths and weaknesses of the leading theories proposed to explain the pathogenesis of HLHS—including hemodynamic disturbances, primary myocardial structural defects, valvar malformations, and genetic or epigenetic alterations that may provoke developmental and anatomic abnormalities. After presenting each model, we propose a novel, comprehensive, and data-driven framework which may assist researchers in developing models for the pathogenesis of the various subtypes of HLHS. Methods: Key findings from human fetal imaging, histopathology, genetic studies, and animal models were considered, as well as the hypothetical contribution of each in observed HLHS phenotypes. The rationales for these findings as causal factors initiating individual HLHS patterns, as well as how they might contribute to HLHS in general, were critically analyzed. Results: The flow theory is strongly supported by animal models and in utero interventions that demonstrate the impact of altered hemodynamics on cardiac morphogenesis. However, the flow theory fails to identify initial causes of disturbed flow or related histological features of HLHS like endocardial fibroelastosis. The myocardial and valve-first models suggest an important role in developmental defects, but do not necessarily have a strong experimental basis that provides explanations for how they mediate HLHS. Genetic studies in patients with HLHS have identified several candidate causal mutations. However, such genetic causes of HLHS exhibit incomplete phenotypic penetrance and clinical impact. A multifactorial framework attempts to integrate these diverse mechanisms and may provide the most coherent explanation that can accommodate the heterogeneity and variable presentation of HLHS. Such a framework may identify multiple forces that drive disease but does not provide useful pathways for future research about HLHS. Conclusions: No single hypothesis has fully explained how HLHS is initiated, progresses, and presents with the clinical conditions that are encountered by cardiac surgeons and cardiologists. The most current models suggest that the spectrum of HLHS reflects acomplex interaction between genetic susceptibility, flow-dependent cardiac remodeling, and environmental factors in utero. A multifactorial model integrates these diverse mechanisms and may provide the most coherent explanation for the various phenotypic variations in HLHS. Based on our analysis of the most current data and the strengths and weaknesses of the current theoretical frameworks, we propose a novel research strategy aimed at identifying specific cardiac progenitor cell populations whose dysregulation may represent a unifying explanation for the etiology of the various phenotypes of HLHS. Based on the arguments made throughout this manuscript that evaluate the various genetic, structural, and hemodynamic models of initiation of disease, we believe that the significant phenotypic variability across the spectrum of HLHS (i.e., the different anatomic subtypes for “classic” HLHS) most likely reflects different underlying etiologies and mechanisms. At the very least, it is very likely that the timing of the insult is critical in determining anatomic subtype. Based on the published data and the arguments within this manuscript, it seems naive to think that there is a single unifying mechanism explain all forms of HLHLS.

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Rationale Lung-protective ventilation protocols use predicted body weight (PBW) to set tidal volumes. However, biases exist in these formulas, with overestimation of lung capacity in older, shorter, female, and non-White patients—groups that experience higher mortality rates during invasive mechanical ventilation (IMV). This study investigated associations between pre-admission forced vital capacity (FVC), driving pressure, and patient outcomes. Methods This multicenter retrospective study included adults (18-95 years old) with pre-admission spirometry who required IMV between 01/01/2016 and 05/31/2025 across the Mayo Clinic, spanning 11 ICUs within 5 hospitals in 4 states. Patients were stratified by FVC/PBW ratio quartiles. The primary outcome was 28-day mortality. Trends were assessed using linear or logistic regression, with FVC/PBW as a continuous variable. Mediation analysis examined pathways between FVC/PBW and mortality, with driving pressure (cm H2O, standardized) as the mediator, and adjusted for covariates including age, sex, SOFA score, and BMI. Absolute risk differences and number needed to harm (NNH) were estimated for key thresholds (e.g. FVC/PBW ≥45 mL/kg, PFTs within 2 years). Results Among 4,839 patients (38.7% female, mean (±SD) age 64.5±13.5 years), FVC/PBW ratio demonstrated substantial individual variation, with a mean of 48.3 ± 13.4 mL/kg. There was systematic variation by demographics (Figure): females had significantly lower ratios than males (45.4 versus 50.2 mL/kg, P &lt; 0.001), and ratios were lower with older age from 52.5 mL/kg in patients &lt;65 to 43.2 mL/kg in those ≥85 years (P &lt; 0.001 for trend). Patients in the lowest FVC/PBW quartile had higher 28-day mortality compared to the highest quartile (26.0% versus 17.0%, P &lt; 0.001) and higher driving pressures (14.0 versus 10.0 cm H2O, P &lt; 0.001; Figure). In mediation analysis (n = 4,147), driving pressure mediated the relationship between FVC and mortality. Each 1-SD increase in FVC/PBW was associated with 0.364-SD lower driving pressure (P &lt; 0.001) and 2.4% lower mortality. The adjusted indirect effect through driving pressure was significant (ACME -0.024, 95% CI: -0.029 to -0.019), accounting for the mortality effect. Sensitivity analyses across binary thresholds, age quartiles, outlier exclusion, and obstructive pathology confirmed robust mediation. Patients with FVC/PBW &lt;45 mL/kg (N = 1,644; 39.6%) had 28-day mortality of 17.8% versus 13.5% for ≥45 mL/kg (risk difference 4.3%, 95% CI 1.8-6.8%; NNH: 23 patients). Conclusions Pre-admission lung function was strongly associated with mortality in adults receiving IMV through driving pressure-mediated pathways. Driving pressure is a modifiable target, especially in patients with smaller lung capacities at highest risk for ventilator-induced lung injury. Further prospective investigation is needed to confirm these findings. This abstract is funded by: National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health (NIH) Grant Number K23HL151671

Abstract Rationale Type-1 inflammation in asthma leads to significant airway level changes independent of Type-2 inflammation and may underlie the severity seen in combined Type1/2 high disease. As IFNs can cause airway epithelial injury and impaired repair, we applied a novel interpretable machine learning algorithm, SLIDE, to analyze the transcriptome of airway epithelial brushings of mild-moderate (MMA) and severe asthma (SA) participants in the Immune Mechanisms in Severe Asthma (IMSA) cohort to identify latent/hidden factors of disease that associate with disease severity. Methods The expression of genes identified by SLIDE as part of a co-expression program was assessed in the full IMSA cohort by severity and in an independent cohort of the NHLBI Severe Asthma Research Program (SARP). We also examined associations of these genes with clinical asthma outcomes in both cohorts. Results SLIDE identified aberrant increased expression of membrane-tethered mucin genes, MUC1 and MUC4. MUC1 appeared in each of 5 significant latent factors associated with greater severity and MUC4 in 2/5. Standard DGE analysis also identified the gene CEACAM5 as a predictor of severity. Pathway analysis of latent factor genes revealed airway keratinization which may contribute to airway remodeling and worsening obstruction over time. Expression of MUC1, MUC4, and CEACAM5 were increased in SA compared to HC in both the full IMSA and separate SARP cohorts (p &lt; 0.001 for all genes in both cohorts). Expression in MMA was consistently lower than in SA in both cohorts, reaching significance in IMSA (p &lt; 0.01) but not consistently in SARP (MUC1 p = 0.04, MUC4 p = 0.27, CEACAM5 p = 0.27). Protein analysis of endobronchial biopsies by immunofluorescence staining showed a trend towards increased MUC1 protein content with evidence of secretion. MUC1, MUC4 and CEACAM5 were negatively correlated with FEV1 % predicted in both cohorts (IMSA: MUC1 r=-0.47, p &lt; 0.01, MUC4 r=-0.47, p &lt; 0.01, CEACAM5 r=-0.62, p &lt; 0.01; SARP: MUC1 r=-0.19, p = 0.05, MUC4 r=-0.29, p &lt; 0.01, CEACAM5 r=-0.51, p &lt; 0.01). All three genes positively correlated with prospective exacerbations in both cohorts (IMSA: MUC1 r = 0.345, p = 0.01, MUC4 r = 0.216, p = 0.08, CEACAM5 r = 0.368, p &lt; 0.01; SARP: MUC1 r = 0.22, p = 0.02, MUC4 r = 0.32, p &lt; 0.01, CEACAM5 r = 0.38, p &lt; 0.01). Conclusions The expression of MUC1, MUC4 and CEACAM5 increased with asthma severity in the airway epithelium and correlated with both prospective exacerbations and obstruction. As pathway analysis of genes in the significant latent factors were associated with airway keratinization aberrant expression of these mucins (with known signaling functions) may contribute to maladaptive repair and airway remodeling that drives obstruction over time, contributing to worse asthma outcomes. This abstract is funded by: NIH

Objectives To compare patients’ perception of their degree of subglottic stenosis to their endoscopic exam findings, Clinical Dyspnea Questionnaire, and peak flow results. Study Design Prospective Multi-Institutional. Setting Tertiary Care Clinic. Methods A study of 50 patients comparing patients’ perception of their degree of subglottic stenosis to their endoscopic exam findings. All patients filled out a Clinical Dyspnea Questionnaire and a 10-point scale reflecting their perceived degree of stenosis in 10% intervals. Surgeons filled out the same scale based on measurements from the patients’ exam. Accuracy was defined as +/-1 on a 10-point scale. Pulmonary function testing, number of dilation procedures undergone, cause of stenosis, and demographic information were collected. Results Data complete for 49/50 patients. 48 (98%) were female, 47 (97.9%) Caucasian, 44 (89.8%) had idiopathic subglottic stenosis, and 28 (58.3%) had Grade I subglottic stenosis on the Cotton-Meyer scale. Spearman correlation coefficient was 0.67 indicating moderate correlation overall but 0.88, or high correlation, for those with normal Body Mass Index. Increased Dyspnea Index scores and higher Body Mass Index were correlated with decreased accuracy. Number of previous procedures was not correlated with accuracy. Higher Body Mass Index was correlated with increased dyspnea and lower peak flow volume. Conclusion Patients with normal Body Mass Index have strong predictive accuracy regarding their degree of subglottic stenosis. Better dyspnea scores were correlated with improved accuracy. There is no standard consensus on subglottic stenosis patient follow up. Prior studies have looked at using peak flow meters and validated questionnaires to monitor symptoms.